The mechanism by which HIV induces a progressive loss of CD4+ T helper cells is not understood. Recent reports support the hypothesis that T cells infected with HIV-1 in vivo are not apoptotic, while uninfected cells are apoptotic. It is possible that HIV offers a protective effect against apoptosis in infected cells. Understanding how HIV-1 prevents apoptosis may allow the development of drugs that would cause the infected cell to apoptose early in infection, thereby potentially slowing the spread of the virus and prolonging the life of an infected person. This proposal will test the hypothesis that HIV-1 protects the infected cell from apoptosis. The hypothesis will be tested by infecting T cells with HIV-1, and allowing the virus to spread in culture, followed by analysis of apoptosis directly or after T cell activation. Alternatively, cells will be transfected with HIV-1 proviral genomes that have been modified to inhibit replication but not gene expression. As above cells will then be analyzed for apoptosis directly or after T cell receptor or Fas ligation, treatments which are known to induce apoptosis in T cell cultures. A determination will be made as to which cells are apoptosing, the HIV-1 expressing cells or the cells in the same culture that are not expressing HIV-1 gene products. This will be accomplished by detecting cells expressing viral gene products by FACS analysis concomitant with analysis for apoptosis by light scatter changes, in situ tailing (IST), or 7 amino-actinomycin D cellular uptake. The genes responsible for the protection will then be mapped in Specific Aim #2.